Visualization of Adverse effect pathways

1. Visualization of Adverse effect pathways HristoAladjov

2. Overview Overview • What are adverse effect pathways ? • Challenges of the Adverse Effect Pathways ? • What are some of the existing solutions for representing pathways ? • Why Adverse Effect Pathways are important for QSAR models ? • The Solution

3. What are Adverse Effect Pathways Overview Generalized Estrogen Receptor (ER) Adverse Effect Pathway MOLECULAR Initiating Event CELLULAR Response TISSUE/ORGAN Response INDIVIDUAL Response POPULATION Response ER Binding Altered Protein Expression Altered proteins Ova-testis Sex Reversal, Altered Behavior, ↓Repro. Skewed Sex Ratios, ↓Year Class Adverse Effect Pathway of Developmental Neurotoxicity in Humans CELLULAR Response MOLECULAR Initiating Event CELLULAR Response TISSUE/ORGAN Response INDIVIDUAL Response AChEBinding Altered Intra-cellular Signaling Altered Cell Structure Brain: Loss of synaptic connect. Behavior: Impaired cognitive function

4. Challenges of the Adverse Effect Pathways Challenges of the Adverse Effect Pathways • Complexity • Multidisciplinary • Lack of unified pathway representation language • Accessibility to the scientific community and the public

5. Existing Solutions Existing Solutions • System biology models advantages • Systematic description of the complex interactions in biological systems • Integrate and analyze complex data from multiple experimental sources • System biology models disadvantages • Exhaustive complexity not focused by the subject of study • Focus on molecular level • Investigating the continuous uncompensated dysfunction • ToxRefDB • Collection of endpoints • ToxCast • Collection of in-vitro cellular assays

6. QSAR models and Adverse Effect Pathways QSAR models and Adverse Effect Pathways • First Rule of QSAR: Select well defined Endpoint • Model different mechanisms/modes of action separately • Separate chemical models from biological effects • Use transparent mechanistically interpretable methods • Use good quality data Inspiring the Next Generation QSAR Models, based on classic rules

7. The online encyclopedia of Adverse effect pathways

8. Effectopedia – Adverse Effect Pathways Representation System Efectopedia.qsari.org • Simple enough to make it manageable, complex enough to be useful • Build the pathways from both ends • Brake the complexity with simple questions • Provide organized slots and global context for integrating individual experts knowledge • Create efficient way of expert collaboration • Create open standard for pathway presentation • Make all data freely accessible online

9. Use Simple Building Blocks Pathway Building Blocks Cause Effect Link • Chemical • Molecular Initiating Event • Effect • Threshold • Dose-Response • Reversible or not • Specific or not • Duration • Molecular Initiating Event • Effect • Endpoint

10. Coordinates in Pathway Space Effect: … male adult human Liver … Gender Life Stage Taxonomy Level of Biological Organization

11. Start form both ends Efectopedia.qsari.org MIE 1 Effect 1 Chemical Endpoint Effect 1 Effect 1 Effect 1 MIE 2 Effect 2 Effect 2 Effect 2 Effect 2 Effect n1 Effect n1 Effect n1 MIE n Effect n

12. Breaking Complexity with simple Questions Efectopedia.qsari.org Effect 1 Effect 2 Effect What Other Downstream effects you know?

13. Breaking Complexity with simple Questions Efectopedia.qsari.org Cause 1 Effect Cause 2 What other causes you know can lead to this effect?

14. Dysfunction Duration as a Cause Effectopedia.qsari.org Link conditions: Duration 1 Endpoint 1 Effect Link conditions: Duration 2 Endpoint 2

15. Demo Effectopedia.qsari.org

16. Technology Free, Platform Independent, Open Source • Based entirely on open source platform independent solutions <? XML ?> • Accessible with standard web browser • Creates search engine optimized static HTML pages for higher visibility • Standard XML based language for direct data import / export • Modular, Plug-in architecture • Open source

17. Benefits Conclusions • QSAR models can be used for what they are good for – predicting molecular initiating events and identifying chemicals with similar behavior without additional animal testing • Provide a global context and new applications of existing experimental data • Create public knowledge repository that stimulate research and modeling efforts • Outline the most frequently used tests in regulatory decision making process to facilitate the search for alternative methods. • Help indentify missing information and facilitate experiment design. • Create focused and effective discussion environment